In contrast, the enhanced insulin sensitivity and normalized glucose levels in response to a calorie restriction (CR) regimen, relative to a control or diet-induced obesity (DIO) regimen, results in lowered serum insulin and IGF-1, and increased IGFBP production, particularly IGFBP1 and 3 (and hence low levels of bioavailable IGF-1) (11). This evidence concerns the gene IGF1 and obesity due to melanocortin 4 receptor deficiency.